Gene mutations have been implicated as a cause of cardiomyopathy. For example, variations in over 40 genes, most of which encode components of the sarcomere, the cytoskeleton, or the nuclear lamina, have been demonstrated or posited to cause dilated cardiomyopathy (DCM) (Ahmad et al. Annual review of genomics and human genetics 2005; 6:185-216; Dellefave L, Mcnally E M. Current Opinion in Cardiology 2010; 25(3):198-204). Further, while clinical evaluation identifies affected or likely-affected family members in 30 to 50% of DCM cases (Michels et al. N Engl J Med 1992; 326(2):77-82; Baig et al. Journal of the American College of Cardiology 1998; 31(1):195; Mestroni et al. Journal of the American College of Cardiology 1999; 34(1):181-90), implicating a genetic etiology, pathogenic mutations have been found in only 20 to 30% of cases (Zimmerman et al. Genet Med 2010; 12(5):268-78).
TTN, the gene encoding titin, has been implicated in cardiomyopathy, but has been incompletely studied due to technical challenges posed by the monumental size of its coding sequence (˜100 kb). Titin is the largest human protein (˜33,000 amino acids) and the third most abundant striated muscle protein (Trinick et al. J Mol Biol 1984; 180(2):331-56)